The retinoids are a group of compounds that are structurally related to vitamin A and that are used in the treatment of many diseases, especially diseases of the skin. Retinoic acid (RA), the most studied metabolite in the vitamin A pathway, exerts a broad range of biologic effects by controlling gene expression. RA binds to and activates the nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR)— transcription factors that link vitamin A metabolism to the transcriptional regulation of specific gene cassettes (Chambon, Faseb J 10, 940-54 (1996); Heyman, et al., Cell 68:397-406 (1992); Shulman, et al., N. Engl. J. Med. 353:604-15 (2005)). Retinoid X receptors also control key metabolic pathways by serving as the obligate heterodimeric partner for multiple steroid hormone nuclear receptor family members, including peroxisome proliferator-activated receptors (PPARs; Shulman, et al., N. Engl. J. Med. 353:604-15 (2005)). PPAR's are known to exist in three different isotypes, PPAR-alpha, PPAR-delta and PPAR-gamma.
RA also plays a role in adipogenesis, a differentiation process regulated by the complex interaction of multiple RXR heterodimeric partners (Fu, et al., Mol. Endocrinol. 19:2437-50 (2005)). RA effects appear to vary as a function of the stage of adipogenesis and relative RAR, PPARγ, and RXR expression (Fu, et al., Mol. Endocrinol. 19:2437-50 (2005); Xue, et al., Mol. Cell. Biol. 16:1567-75 (1996)). Early in adipogenesis, RA blocks differentiation, whereas, after 48 hours of differentiation, RA promotes fat cell formation (Xue, et al., Mol. Cell. Biol. 16:1567-75 (1996)). Divergent effects of RA on adipogenesis likely derives from differential actions of specific configurations of RA (all trans vs 9 cis RA) and the interaction of these different molecules with distinct nuclear receptors, namely RAR and RXR). This data highlights the importance of specific retinoid molecules and metabolites.
In contrast to the broad range of biological effects associated with RA, a role for Rald outside the eye remains essentially unknown (Napoli, Prog. Nucleic Acid Res. Mol. Biol. 63:139-88 (1999)). Rald is considered primarily a precursor for RA formation (Duester, et al., Chem. Biol. Interact. 143-144:201-10 (2003); Duester, Eur. J. Biochem. 267:4315-24 (2000)). Alcohol dehydrogenases (Adh) oxidize retinol (vitamin A) to Rald while retinaldehyde dehydrogenases (Raldh) help reduce cellular levels by oxidizing Rald to RA (Duester, et al., Chem. Biol. Interact. 143-144:201-10 (2003)). A toxicology study on citral, an inhibitor of Raldh, demonstrated that citral at high doses was well tolerated in rats and that rats fed a diet with citral weighed less than animals fed a citral free diet (Ress, et al., Toxicol. Sci. 71:198-206 (2003)).